This invention is directed to treating malignant tumors in vivo utilizing the compound 8-chloroadenosine 3',5'-cyclic phosphate. This compound and other related adenine and adenosine compounds are prepared by two novel syntheses utilizing hydrogen chloride and m-chloroperoxybenzoic acid in a suitable solvent in the first synthesis and N-chlorosuccinamide and acetic acid in a suitable solvent in the second synthesis.
While the arsenal of chemotherapeutic agents for treating neoplastic diseases includes a number of clinically useful agents, control of malignant tumors in warm blooded animals still remains a much sought after goal.
In a study reported from the People's Republic of China but not confirm elsewhere, 8-bromoadenosine 3',5'-cyclic phosphate was noted as inhibiting the solid form of uterine tumor 14 Ehrlich carcinoma, sarcoma-180 and reticulum-cell sarcoma in mice. An abstract of this study appeared in a Cancergram of the International Cancer Research Data Bank, Series CB14 Number 80/03, March 1980, published by the United States Department Health, Education and Welfare National Institute of Health, National Cancer Institute. In contrast to this report, in other studies 8-bromoadenosine 3',5'-cyclic phosphate has been found to be inactive as an antitumor agent in cell culture.
Contemporaneously with the above report, Y. S. Cho-chung, J. Cyclic Nucleotide Res. 6: 163, 1980, reported certain investigative studies on an antagonistic interaction between estrogen and adenosine 3',5'-cyclic monophosphate (hereinafter alternately referred to as cAMP) and what role this might have in the control of growth of hormone-dependent mammary tumors.
In studying the effects of mediated control of tumor growth by adenosine 3',5'-cyclic phosphate, Cho-chung has elucidated that cAMP functions by binding to a cAMP receptor protein which has two different cAMP binding sites. The cAMP receptor protein is a regulatory subunit of a cAMP dependent protein kinase. There apparently is site selectivity in binding to one or the other of two sites. This activity can thus be described as site 1-selectivity and site 2-selectivity.
In view of the inability of current cancer chemotherapeutics to successfully control all neoplastic diseases, it is evident that there exists a need for new and additional cancer chemotherapeutic agents. Further there exist a need for new and better preparative procedures for the syntesis of such new and additional cancer chemotherapeutic agents.
8-chloroadenosine 3',5'-cyclic phosphate was first reported by inventor R. K. Robins of this invention and his other co-authors in K. Muneyama et al, J. Charbohyd. Nucleosides Nucleotides, 1, 55, 1974. It has now been found that 8-chloroadenosine 3',5'-cyclic phosphate (hereinafter alternately also identified as 8-chloro cAMP), exhibits such significant antitumor activity so as to be useful as an antitumor agent in vivo. Further, two novel preparative synthesis yield 8-chloroadenosine compounds such as 8-chloroadenosine 3',5'-cyclic phosphate directly from respective adenosine precursors.